2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (hereinafter, referred to as “blonanserin”), which is a serotonin-dopamine antagonist (SDA), is disclosed in JP-B-7 (1995)-47574. Blonanserin is useful as an antipsychotic agent since it has higher affinity for dopamine D2 receptor and serotonin 5-HT2 receptor than haloperidol which is an existing antipsychotic agent.
Regarding to oral administration of blonanserin to animals, Michiaki Matsuda, et al., J. Pharm. Biomed. Anal., 15, 1449-1456, 1997 (hereinafter referred to as “Reference 1”) reports the time course of blood level of blonanserin and metabolites thereof, therein it is disclosed that blonanserin administered orally to animals such as a rat is metabolized to a metabolite thereof through first-pass effect.
In general, a percutaneous absorption route is known as an administration route characterized by maintaining the drug concentration in the blood more continuously than an oral administration route and by avoiding first-pass effect. In addition, a percutaneous absorption route also has an advantage that it is not affected by diet. Especially, a tape preparation which is one of transdermal administrations is useful from the viewpoint that it is easy to check out an administration and a discontinuation.
As a percutaneous absorption preparation comprising an antipsychotic agent, a transdermal formulation comprising olanzapine (WO 97/09985), a transdermal formulation comprising risperidone (WO 96/31201), and a transdermal formulation comprising perospirone (WO 2006/025516) have already been known.
In general, it is uncommon that percutaneous administration can let a sufficient amount of a medicament penetrate a skin to exert the activity of the medicament. Therefore, it is necessary to study the permeability of a medicament itself, or consider the addition of an agent that can make a skin permeation of a medicament accelerated. However, it is difficult to foresee such permeability of a medicament or the effect of such additive agent because the characteristics may easily be changed depending on the kind of a medicament. Therefore, it is thought that it impossible or very difficult to develop a percutaneous absorption formulation using a medicament useful as an oral preparation. In addition, it is also difficult to foresee if first-pass effect can be avoided via percutaneous route, from the same reason.
Therefore, it is very expectant that the above-mentioned useful antipsychotic agent: blonanserin will be developed as a percutaneous absorption formulation from the viewpoint of medical needs and pharmacokinetic effect. However, it has been thought that the development thereof is difficult because the skin permeability of blonanserin or the avoidance effect for first-pass effect via percutaneous route has not been resolved enough.
On the other hand, as some examples of a combination of an antipsychotic agent and another medicament, WO 2002/053140 discloses a composition comprising a norepinephrine reuptake inhibitor and a neuroleptic agent (antipsychotic agent), JP-A-2002-308801 discloses a composition comprising a serotonin reuptake inhibitor and an atypical antipsychotic agent, and JP-A-2006-505489 discloses a simultaneous administration of a valproate compound and an atypical antipsychotic agent, wherein in each publication blonanserin is exemplified as an antipsychotic agent, and percutaneous administration is described as one of the administration routes.
However, these publications are directed to the treatment for psychosis with a combination of 2 kinds of medicaments, blonanserin is just one example of antipsychotic agents that may be added to the combination, and further there is no example thereof. Furthermore, these publications do not describe any practical description about a composition or an effect as a percutaneous absorption preparation. After all, these publications did not disclose anything that blonanserin was applied for a percutaneous absorption preparation. Therefore, it was actually impossible to develop a percutaneous absorption preparation comprising blonanserin based on these publications.